Process for production of piperidine derivatives

ABSTRACT

Processes are disclosed for preparing piperidine derivative compounds of the formulae I, II or III: 
                         
The processes involve reacting a compound of formula Ia, IIa or IIIa
 
                         
with isobutyrate or an isobutyrate equivalent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.10/943,276, filed Sep. 17, 2004, the entire disclosure of which isincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to processes for the production ofpiperidine derivatives.

BACKGROUND OF THE INVENTION

Fexofenadine,4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α-α-dimethylphenylaceticacid, formerly known as terfenadine carboxylic acid metabolite, is apotent non-sedating antihistamine sold by Aventis in the United Statesunder the tradename ALLEGRA® and elsewhere in the world under thetradename TELFAST®.

The importance of commercially viable syntheses of fexofenadine isattested to by the scores of patents to fexofenadine processes.Piperidine derivatives related to fexofenadine are disclosed in thefollowing U.S. Pat. Nos. 4,254,129; 4,254,130; 4,285,957; and 4,285,958.In these patents,4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid and related compounds are prepared by alkylation of a substitutedpiperidine derivative of the formula:

with an ω-haloalkyl substituted phenyl ketone of the formula:

wherein the substituents halo, R¹, R², n, Z, and R⁶ are described incolumn 6 of U.S. Pat. No. 4,254,130.

U.S. Pat. No. 4,254,130 indicates that ω-haloalkyl substituted phenylketones, wherein Z is hydrogen, are prepared by reacting an appropriatestraight or branched lower alkyl C₁₋₆ ester of α-α-dimethylphenylaceticacid with a compound of the following formula:

under the general conditions of a Friedel-Crafts acylation, wherein haloand m are described in column 11 of U.S. Pat. No. 4,254,129. Thereaction is carried out in carbon disulfide as the preferred solvent.

A more recent approach via Friedel-Crafts acylation with succinicanhydride, condensation with the piperidine and reduction of the ketoneand amide carbonyls has issued as U.S. Pat. No. 6,743,941.

It has been found that the Friedel-Crafts methods have two significantshortcomings: (1) only acyl halides or anhydrides can be used; (2) inthe particular case of the fexofenadine intermediate phenyl ketones, ahigher regioselectivity of the Friedel-Crafts acylation would bedesirable.

In another approach, which is the subject of a series of patents toD'Ambra and others (U.S. Pat. Nos. 5,589,487; 6,153,754 and 6,201,124),fexofenadine is synthesized by a regioselective method employingnon-Friedel-Crafts acylation. The processes of the D'Ambra patentsinvolve acylation of an aromatic ring at a position alreadypara-substituted with a reactive species. Acylation can be carried outby a variety of techniques, including a butyl derivative acylatingagent, a 4-(α,α-disubstituted)-toluic acid derivative acylating agent,or an organometallic coupling reaction. Since such procedures do notinvolve replacement of hydrogen on an aromatic ring, they aredistinguished from electrophilic aromatic substitutions like theFriedel-Crafts acylation reaction.

Other procedures for producing fexofenadine are disclosed in PCTApplication Nos. WO95/00482, WO94/03170, and WO95/00480. A more recentapproach is outlined in US published application 2003/0166682, in whichan intermediate nitrile is hydrolyzed to fexofenadine.

The present invention is directed toward an improved process forpreparation of fexofenadine.

SUMMARY OF THE INVENTION

The present invention relates to processes for preparing piperidinederivative compounds of the formulae I, II or III:

whereinR⁴ is H, alkyl or aryl;A, B, and D are the substituents of their rings, each of which may bedifferent or the same, and are selected from the group consisting ofhydrogen, fluorine, chlorine, alkyl, aryl, hydroxyl, alkoxy, andaryloxy. The process comprises providing a compound of formula Ia, IIaor IIIa

wherein X is any group displaceable via an oxidative metallic addition,and converting the compound of formula Ia, IIa or IIIa to I, II or IIIrespectively by reacting with isobutyrate or an isobutyrate equivalent.

In another aspect the invention relates to a process for preparing anα,α-dimethyl-4-acylphenylacetate of the formula V, VI or VII:

wherein LG is a leaving group displaceable by a secondary amine. Theprocess comprises providing a compound of formula Va, VIa or VIIa:

and converting the compound of formula Va, VIIa or VIIa to V, VI or VIIrespectively by reacting with isobutyrate or an isobutyrate equivalent.

In another aspect the invention relates to compounds of formula

in which X^(a) is —OSO₂R⁵, —N₂ ⁺, —OH or —B(OR⁶)(OR⁷), wherein R⁵ ischosen from fluoro, alkyl, fluoroalkyl, aryl, heteroaryl and substitutedaryl; and R⁶ and R⁷ are chosen from H and C₁-C₂₀ hydrocarbon.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this application, various references are referred to. Thedisclosures of each of these publications in their entireties are herebyincorporated by reference as if written herein.

DEFINITIONS

In this specification the terms and substituents are defined whenintroduced and retain their definitions throughout.

Alkyl is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof. Lower alkyl refers to alkyl groupsof from 1 to 6 carbon atoms. Examples of lower alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like.Preferred alkyl groups are those of C₂₀ or below. Cycloalkyl is a subsetof alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbonatoms. Examples of cycloalkyl groups include c-propyl, c-butyl,c-pentyl, norbornyl and the like.

C₁ to C₂₀ Hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryland combinations thereof. Examples include phenethyl, cyclohexylmethyl,camphoryl and naphthylethyl.

Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of astraight, branched, cyclic configuration and combinations thereofattached to the parent structure through an oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy andthe like. Lower-alkoxy refers to groups containing one to four carbons.

Oxaalkyl refers to alkyl residues in which one or more carbons has beenreplaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyland the like.

Acyl refers to groups of from 1 to 8 carbon atoms of a straight,branched, cyclic configuration, saturated, unsaturated and aromatic andcombinations thereof, attached to the parent structure through ancarbonyl functionality. One or more carbons in the acyl residue may bereplaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples includeacetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl,benzyloxycarbonyl and the like. Lower-acyl refers to groups containingone to four carbons.

Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromaticring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9-or 10-membered aromatic or heteroaromatic ring system containing 0-3heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-memberedaromatic or heteroaromatic ring system containing 0-3 heteroatomsselected from O, N, or S. The aromatic 6- to 14-membered carbocyclicrings include, e.g., benzene, naphthalene, indane, tetralin, andfluorene and the 5- to 10-membered aromatic heterocyclic rings include,e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole,furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine,pyrazine, tetrazole and pyrazole.

Arylalkyl means an alkyl residue attached to an aryl ring. Examples arebenzyl, phenethyl and the like.

Substituted alkyl, aryl, cycloalkyl, etc. refer to alkyl, aryl orcycloalkyl, wherein up to three H atoms in each residue are replacedwith halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy(also referred to as alkoxycarbonyl), carboxamido (also referred to asalkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino,dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino,amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, orheteroaryloxy.

The term “halogen” means fluorine, chlorine, bromine or iodine.

Terminology related to “protecting”, “deprotecting” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes which involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group that isused to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups”. Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry [See e.g. ProtectiveGroups in Organic Synthesis by T. W. Greene and P. G. M. Wuts, 2ndEdition; John Wiley & Sons, New York (1991)].

The abbreviations Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl,phenyl, trifluoromethanesulfonyl, toluensulfonyl and methanesulfonylrespectively. A comprehensive list of abbreviations utilized by organicchemists (i.e. persons of ordinary skill in the art) appears in thefirst issue of each volume of the Journal of Organic Chemistry. Thelist, which is typically presented in a table entitled “Standard List ofAbbreviations” is incorporated herein by reference.

The present invention relates to processes for preparing piperidinederivative compounds of the formulae I, II or III. In these compounds,A, B, and D may be different or the same, and are selected from thegroup consisting of hydrogen, fluorine, chlorine, alkyl, aryl, hydroxyl,alkoxy, and aryloxy. Examples of compounds of formula I, II and III arethose in which all of A, B and D are hydrogen and those in which A ishydrogen and B and D are halogens, e.g. fluorine, at the para positions.

The compounds of formula I may be reduced with hydrides, boranes orother reducing agents, as well known in the art, [see e.g. U.S. Pat.Nos. 5,589,487 and 6,743,941] to produce fexofenadine. The compounds offormula II in which R⁴ is alkyl or aryl may be hydrolyzed to producefexofenadine. When R⁴, A, B, and D are all hydrogen, the compounds offormula II are fexofenadine and are produced by a direct single-stepreaction. The compounds of formula III may be converted to compounds offormula I by the procedure described by Kawai et al. J. Org. Chem. 59,2620-2622 (1994).

The compounds of formulae I, II and III are prepared by a process inwhich a compound of formula Ia, IIa or IIIa

is reacted with isobutyrate or an isobutyrate equivalent. Thesubstituent X may be chlorine, bromine, iodine, —OSO₂R⁵, —N₂ ⁺, —OH or—B(OR⁶)(OR⁷), wherein R⁵ is chosen from fluoro, alkyl, fluoroalkyl,aryl, heteroaryl and substituted aryl; R⁶ and R⁷ are chosen from H andC₁-C₂₀ hydrocarbon, including cyclic structures, e.g. dioxaboroles.Compounds in which X is —OSO₂R⁵, may be prepared from compounds in whichX is —OH by sulfonation with the appropriate sulfonyl halide oranhydride in the presence of a base, as well known in the art. Compoundsin which X is —N₂ ⁺ may be prepared from the corresponding aniline ornitrobenzene by processes well known in the art. [See e.g. Herr et al.Org. Proc. Res. Dev. 6, 677-681 (2002) and Siegrist et al. Org. Proc.Res. Dev. 7, 429-431 (2003).] Compounds in which X is —B(OR⁶)(OR⁷) maybe prepared from the corresponding halides by the method of Ishiyama etal. [J. Org. Chem. 60, 7508-7510 (1995)].

The isobutyrate or an isobutyrate equivalent may be of the formula VIIIor IV:

wherein R⁸ is a protecting group for a ketene acetal, [See ProtectiveGroups in Organic Synthesis by T. W. Greene, op. cit.] The protectinggroup for a ketene acetal may be a simple alkyl, such as methyl orethyl, a dialkylphosphoryl or, preferably, a trialkylsilyl group, suchas trimethylsilyl or t-butyldimethylsilyl. The compounds of formula VIIIare commercially available or are synthesized by procedures well-knownin the art. The compounds of formula IV are also known in the art andmay be synthesized as described by Liu and Hartwig [J. Am. Chem. Soc.126, 5182-5191 (2004)]. The isobutyrate or isobutyrate equivalent mayalso be of the formulae IX-XII:

although these equivalents are less preferred. As will be evident to theartisan, the conditions for the final hydrolysis of ester to carboxylateto prepare fexofenadine will be modified to accommodate the thioester oramide.

The coupling reactions are carried out in a suitable solvent in thepresence of an appropriate catalyst for about 1 to 120 hours and attemperatures of about −78° C. to the reflux temperature of the solvent.Suitable solvents for coupling include: hydrocarbon solvents, such asbenzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons, suchas chlorobenzene, dichloroethane, methylene chloride, chloroform, orcarbon tetrachloride; carbon disulfide; dimethylformamide; etherealsolvents, like tetrahydrofuran and diethylether; or dioxane.

The reaction between the compounds of formulae I-III and IV or VIII iscatalyzed by a transition metal. The transition metal catalyst is aGroup 8B transition metal, that is, a metal selected from iron, cobalt,nickel, ruthenium, rhodium, palladium, osmium, iridium, and platinum.More preferably, the Group 8 metal is palladium, platinum, or nickel,and most preferably, palladium. The Group 8 metal may exist in anyoxidation state ranging from the zero-valent state to any highervariance available to the metal. The preferred catalysts forcondensations are palladium acetate, palladium chloride, palladiumbromide, palladium acetylacetonate, bis(tri-o-tolyl)phosphine palladiumdichloride, tetrakis(triphenylphosphine)palladium [(Ph₃P)₄Pd] andbis(dibenzylideneacetone) palladium [(dba)₂Pd].

The chelating ligand my be a neutral molecule or charged ion. Thechelating ligand is also required to contain at least one element fromGroup 5B of the Periodic Table, preferably, at least one element ofnitrogen, phosphorus, or arsenic, and more preferably nitrogen orphosphorus. Examples include tri-(o-tolyl)phosphine andtriphenylphosphine. Preferred ligands for the coupling with VIII are1,1′-bis(di-o-tolylphosphino)ferrocene (DTPF);1,1′-bis(diphenylphosphino)ferrocene (DPPF);1-di-t-butylphosphino-2-methylaminoethyl ferrocene;[2′-(diphenylphosphino)[1,1′-binaphthalen]-2-yl]diphenylphosphine oxide(BINAP) and 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl (tol-BINAP).Preferred ligands for the coupling with IV are trialkyl ortriarylphosphines, such as tri-t-butylphosphine.

Conditions for metal catalyzed couplings are described with referencesin Diederich and Stang, Metal-Catalyzed Cross-Coupling Reactions;Wiley-VCH (1998) and in particular detail in U.S. Pat. No. 6,057,456. Inaddition to palladium catalysts, as described below, one may employother transition metals.

In formula Ia-IIIa, as well as in Va and VIa below, X is preferablybromide or triflate, as shown in the examples below, but othersubstituents suitable for metal catalyzed coupling reactions may be usedin their place. For example, diazonium salts may be used as described inSakakura et al JCSP1 1994, 283-288. It will be apparent to the person ofskill that, when A is chlorine, in order to have reasonable yields ofsingle positional isomers, X should be other than chlorine.

When the starting material is of the formula VIII, a base must be used.Non-limiting examples of suitable bases include alkali metal hydroxides,such as sodium and potassium hydroxides; alkali metal alkoxides, such assodium t-butoxide; metal carbonates, such as potassium carbonate, cesiumcarbonate, and magnesium carbonate; alkali metal aryl oxides, such aspotassium phenoxide; alkali metal amides, such as lithium amide;tertiary amines, such as triethylamine and tributylamine;(hydrocarbyl)ammonium hydroxides, such as benzyltrimethylammoniumhydroxide and tetraethylammonium hydroxide; diaza organic bases, such as1,8-diazabicyclo[5.4.0]-undec-7-ene and1,8-diazabicyclo-[2.2.2.]-octane, and silyl compounds such as potassiumhexamethyldisilazide (KN(Si(CH₃)₃)₂). Preferably, the base is an alkalialkoxide or a silyl-containing compound. The molar ratio of base to Ia,IIa or IIIa ranges from about 1:1 to about 3:1, and is usually betweenabout 1:1 and 2:1.

When the starting material is of the formula IV, a metal salt is usedinstead of a base. Exemplary salts include ZnF₂ and Zn(OtBu)₂.

In another aspect the invention relates to a process for preparing anα,α-dimethyl-4-acylphenylacetate of the formula V, VI or VII:

wherein LG is a leaving group displaceable by a secondary amine,particularly a group displaceable by a piperidine, for example a halogenor a sulfonate. LG is preferably bromine, chlorine, methansulfonate,toluenesulfonate or triflate. The process comprises providing a compoundof formula Va, VIIa or VIIa:

and converting the compound of formula Va, VIIa or VIIa to V, VI or VIIrespectively by reacting with isobutyrate or an isobutyrate equivalent.The process parallels the process shown above for I, II and III from 1a,IIa and IIIa in that the reaction conditions and reagents aresubstantially the same. Compounds of formula Va and VIa, in which A ishydrogen are commercially available from Acros Organics, Geel, Belgium.The compounds of formula VIIa may be prepared according to the method ofGodt [J. Org. Chem. 62, 7471 (1997)]:

A useful iron-catalyzed process, which could be used to synthesize anyof 1-VII, is described by Fürstner et al J. Am. Chem. Soc. 124,13856-13863 (2002):

The α,α-dimethyl-4-acylphenylacetates of the formulae V, VI and VII maybe further reacted with a piperidine derivative as described in U.S.Pat. Nos. 4,550,116; 5,750,703; 6,153,754; 6,242,606 and others.Exemplary processes that fall within the scope of the invention areillustrated in the schemes below for the synthesis of fexofenadine.These schemes also illustrate the interrelatedness of the processes andintermediates.

Example 1

One gram of 9 was dissolved in 20 mL of DMF and 18 mg of P(tBu)₃, 41 mgof Pd(dba)₂, 230 mg of ZnF₂ and 1.2 g of 5 were added. A mixture wasstirred at 80° for 18 hours, cooled to room temperature, diluted withether and washed with water. The organic layer was dried over sodiumsulfate, filtered and stripped in vacuo. The resulting product was flashchromatographed on silica gel using 4:1 hexane ethyl acetate to yield1.0 g (91%) of 10. A repeat of the reaction on larger scale using 15 gof 9 provided 15.2 g (93%) of 10.

Example 2

Five grams of 9 was dissolved in 50 mL of methylene chloride and cooledto 0° C. To the solution was added 5.78 g of trimethylsilyl iodide. Themixture was stirred for 30 minutes and excess sodium bisulfite solutionwas added with vigorous stirring at room temperature. The layers wereseparated and the aqueous layer extracted twice with methylene chloride.Combined organic layers were dried, filtered and stripped in vacuo toprovide 7.7 g (98%) of 1. The reaction was repeated on a larger scaleusing 15 g of 9 to produce 22.5 g of 1 (96%) yield.

Example 3

Six grams of potassium carbonate, 5.8 g of piperidine 2 and 7.6 g of 1were combined in 100 mL of DMF. The suspension was stirred at roomtemperature until TLC in 4:1 hexane-ethyl acetate indicated a completereaction. The reaction mixture was poured into 400 mL of water andextracted three times with methylene chloride. The combined organicextracts were dried, filtered and reduced in vacuo. The resultingproduct was flash chromatographed on silica gel using ethyl acetatecontaining 10% triethylamine to yield 7.0 g (66%) of 3.

Example 4

Seven grams of 3 was dissolved in 100 mL of methanol, cooled to 0° C.and 1.1 g of sodium borohydride was added. The mixture was stirred 1hour, concentrated and partitioned between ethyl acetate and saturatedaqueous sodium bicarbonate. The bicarbonate layer was extracted twicewith ethyl acetate, the combined organic layers were dried over sodiumsulfate and the solution was reduced in vacuo to provide 7.0 g (100%) of4.

Example 5

Two grams of 4 was dissolved in 30 mL of DMF. To this were added 16.2 mgof P(tBu)₃, 36.6 mg of Pd(dba)₂, 209 mg of ZnF₂ and 1.056 g of 5. Themixture was heated at 80° C., cooled, diluted with ether and worked upas in example 1. The resulting product was flash chromatographed onsilica gel using 9:1 ethyl acetate-triethylamine to provide 450 mg(21.4%) of 7.

Example 6

One hundred fifty milligrams of 7 was slurried in 5 mL of water and 10mL of methanol. To the slurry was added 175 mg of sodium hydroxide. Theslurry was refluxed for one hour, cooled to room temperature and themethanol removed in vacuo. The resulting aqueous solution wasdistributed between water and chloroform, the chloroform layer wasdiscarded, the aqueous layer was adjusted to pH 2.3 and extracted withchloroform. The organic layer was dried, filtered and reduced in vacuoto provide fexofenadine.

Example 7

Five grams of 1 was combined with 3.8 g of 2 and 2.0 g of potassiumcarbonate and 80 mL of DMF. The mixture was stirred at room temperaturefor two hours, poured into 400 mL of water and extracted three timesinto methylene chloride. The combined organic layers were dried,filtered and reduced in vacuo. The resulting product was flashchromatographed on silica gel using 9:1 ethyl acetate-triethylamine toprovide 4.2 g (60%) of 3.

Example 8

Two grams of 3, 90 mg of P(tBu)₃, 300 mg of Pd(dba)₂, 250 mg of ZnF₂ and1.1 g of 5 were dissolved in 330 mL of DMF under argon. The mixture washeated to 80° for two hours, cooled to room temperature, diluted withether and worked up as described in example 1. The resulting product wasfiltered through silica to provide 1.3 g (62%) of 6.

Example 9

Two grams of 20, 170 mg of P(tBu)₃, 560 mg of Pd(acac)₂, 474 mg of ZnF₂and 2.0 g of 5 were combined in 50 mL of DMF under argon. The mixturewas heated to 80° C. and monitored by HPLC. When reaction was complete,the mixture was cooled to room temperature and 250 mL of water wasadded. The mixture was extracted three times with ether, dried, filteredand reduced in vacuo. The resulting product was flash chromatographed in4:1 hexane-ethyl acetate to provide 1.89 g (85%) of 8.

Example 10

Two grams of the triflate analog of 20 were reacted as in the foregoingexample with 134 mg P(tBu)₃, 433 mg of Pd(acac)₂, 375 mg of ZnF₂ and1.58 g of 5 to provide 1.56 g (90% yield) of 8.

The invention claimed is:
 1. A process for preparing a piperidinederivative compound of formula III:

wherein R⁴ is selected from the group comprising H, alkyl, and aryl; A,B, and D are the substituents of their rings, each of which may bedifferent or the same, and are selected from the group consisting ofhydrogen, fluorine, chlorine, alkyl, aryl, hydroxyl, alkoxy, andaryloxy; said process comprising: (a) reacting a compound of formulaVIIa

wherein X is a group chosen from chlorine, bromine, iodine, —OSO₂R⁵, anddiazonium salt displaceable via oxidative metallic addition; and LG is aleaving group displaceable by a secondary amine, said leaving groupchosen from chlorine, bromine, iodine, and —OSO₂R⁵, wherein R⁵ is chosenfrom alkyl, fluoro, fluoroalkyl, aryl, and substituted aryl, or LG is agroup able to be converted to said leaving group displaceable by asecondary amine, said leaving group chosen from chlorine, bromine,iodine, and —OSO₂R⁵; with an isobutyrate equivalent of formula IV

wherein R⁸ is a trialkylsilyl, in the presence of a transition metalcatalyst having a metal selected from the group comprising of Ni and Pd,and ZnF₂ to provide a compound of formula VII

(b) reacting the compound of formula VII with a piperidine compound offormula IX

in the presence of a base to provide the compound of formula III.
 2. Aprocess according to claim 1, wherein the compound of formula VII, inwhich A is hydrogen and LG is a methane or toluene sulfonate, isprepared by reacting a compound of formula VIIab

with the compound of formula IV, followed by reaction withmethanesulfonyl chloride or toluenesulfonylchloride.
 3. A processaccording claim 1 wherein X is displaceable by the isobutyrateequivalent of formula IV by reaction in the presence of a phosphorouscompound chosen from trialkyl phosphine, triaryl phosphine, and mixedalkyl/aryl phosphine, and the transition metal catalyst.
 4. A processaccording to claim 1 wherein R⁸ is trimethylsilyl.
 5. A processaccording claim 1 for preparing a piperidine derivative compound offormula III wherein A, B and C are hydrogen and R⁴ is methyl,comprising: (a) reacting a compound of formula XV

with an isobutyrate equivalent of formula IVa

in the presence of Pd(0) catalyst, a trialkyl or triaryl phosphine, andZnF₂ to provide a compound of formula XVIII

(b) converting the compound of formula XVIII to a compound of formulaXVIIIa

(c) reacting the compound of formula XVIIIa with a piperidine compoundof formula XIXa

in the presence of a base to provide a compound of formula 18


6. A process according to claim 5 wherein, the compound of XV isprepared by reacting a compound of formula XVa

with 1-bromo-4-iodobenzene in the presence of a transition metalcatalyst.
 7. A process for preparing a piperidine derivative compound offormula II

wherein A, B, C and R⁴ are hydrogen, comprising: (a) reacting a compoundof formula XV

with an isobutyrate equivalent of formula IVa

in the presence of Pd(0) catalyst, a trialkyl or triaryl phosphine, andZnF₂ to provide a compound of formula XVIII

(b) converting the compound of formula XVIII to a compound of formulaXVIIIa

(c) reacting the compound of formula XVIIIa with a piperidine compoundof formula XIXa

in the presence of a base to provide a compound of formula 18

(d) oxidizing the acetylene in compound 18 to a ketone, reducing theketone to an alcohol and saponifying the methyl ester to providefexofenadine.